EP0595311B1 - Pharmaceutical composition consisting of flupirtin and morphine for the treatment of pain and to avoid a morphine addiction - Google Patents
Pharmaceutical composition consisting of flupirtin and morphine for the treatment of pain and to avoid a morphine addiction Download PDFInfo
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- EP0595311B1 EP0595311B1 EP93117472A EP93117472A EP0595311B1 EP 0595311 B1 EP0595311 B1 EP 0595311B1 EP 93117472 A EP93117472 A EP 93117472A EP 93117472 A EP93117472 A EP 93117472A EP 0595311 B1 EP0595311 B1 EP 0595311B1
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- Prior art keywords
- morphine
- flupirtine
- addiction
- flupirtin
- pain
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- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 title claims abstract description 65
- 229960005181 morphine Drugs 0.000 title claims abstract description 32
- JUUFBMODXQKSTD-UHFFFAOYSA-N N-[2-amino-6-[(4-fluorophenyl)methylamino]-3-pyridinyl]carbamic acid ethyl ester Chemical compound N1=C(N)C(NC(=O)OCC)=CC=C1NCC1=CC=C(F)C=C1 JUUFBMODXQKSTD-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 239000008194 pharmaceutical composition Substances 0.000 title abstract 2
- 208000008013 morphine dependence Diseases 0.000 title 1
- 229960003667 flupirtine Drugs 0.000 claims abstract description 19
- 150000003839 salts Chemical class 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 2
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- 230000000202 analgesic effect Effects 0.000 abstract description 12
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- 238000002474 experimental method Methods 0.000 description 5
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- 229940035676 analgesics Drugs 0.000 description 4
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- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- UZHSEJADLWPNLE-GRGSLBFTSA-N naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 description 2
- 229960004127 naloxone Drugs 0.000 description 2
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- TVYLLZQTGLZFBW-ZBFHGGJFSA-N (R,R)-tramadol Chemical compound COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-ZBFHGGJFSA-N 0.000 description 1
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 1
- IVVNZDGDKPTYHK-JTQLQIEISA-N 1-cyano-2-[(2s)-3,3-dimethylbutan-2-yl]-3-pyridin-4-ylguanidine Chemical compound CC(C)(C)[C@H](C)N=C(NC#N)NC1=CC=NC=C1 IVVNZDGDKPTYHK-JTQLQIEISA-N 0.000 description 1
- USSIQXCVUWKGNF-UHFFFAOYSA-N 6-(dimethylamino)-4,4-diphenylheptan-3-one Chemical compound C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 USSIQXCVUWKGNF-UHFFFAOYSA-N 0.000 description 1
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 206010052804 Drug tolerance Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010021118 Hypotonia Diseases 0.000 description 1
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102000003840 Opioid Receptors Human genes 0.000 description 1
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- 239000002221 antipyretic Substances 0.000 description 1
- 229940125717 barbiturate Drugs 0.000 description 1
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- RMRJXGBAOAMLHD-IHFGGWKQSA-N buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-IHFGGWKQSA-N 0.000 description 1
- 229960001736 buprenorphine Drugs 0.000 description 1
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- 229960002896 clonidine Drugs 0.000 description 1
- 229960003920 cocaine Drugs 0.000 description 1
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- 239000003085 diluting agent Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
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- 230000002743 euphoric effect Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000000380 hallucinogen Substances 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
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- 238000010253 intravenous injection Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 240000004308 marijuana Species 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- 229960001797 methadone Drugs 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 239000011707 mineral Chemical class 0.000 description 1
- 230000036640 muscle relaxation Effects 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 239000004081 narcotic agent Substances 0.000 description 1
- 229960001027 opium Drugs 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- VOKSWYLNZZRQPF-GDIGMMSISA-N pentazocine Chemical compound C1C2=CC=C(O)C=C2[C@@]2(C)[C@@H](C)[C@@H]1N(CC=C(C)C)CC2 VOKSWYLNZZRQPF-GDIGMMSISA-N 0.000 description 1
- 229960005301 pentazocine Drugs 0.000 description 1
- 229960000482 pethidine Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229960002310 pinacidil Drugs 0.000 description 1
- 235000008476 powdered milk Nutrition 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000000384 rearing effect Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 230000003033 spasmogenic effect Effects 0.000 description 1
- 230000001148 spastic effect Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229960004380 tramadol Drugs 0.000 description 1
- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
Definitions
- the morphine obtained from opium the dried milk juice of unripe poppy capsules (Papaver somniferum), has been used since its isolation by Serener (1806) in the form of the hydrochloride as a remedy for severe pain.
- Serener 1806
- this analgesic for example in tumor patients, there is a risk of developing an addiction and developing tolerance (morphinism).
- Pentazocin and buprenorphine are also subject to narcotics law due to their addictive potential.
- Tramadol is only about 1/10 - 1/5 as potent as morphine, but so far it has no known addiction potential.
- morphine Since morphine has no anti-inflammatory effect, this deficit in the morphine effect can be compensated for by combining morphine with anti-inflammatory or anti-pyretic analgesics.
- morphine Since morphine has no anti-inflammatory effect, this deficit in the morphine effect can be compensated for by combining morphine with anti-inflammatory or anti-pyretic analgesics.
- Vergoni et al. (Life Sci., 50 (16), pages 135-138 (1992)) the potentiating effects of pinacidil on the analgesic effect of morphine.
- the aim of all experiments is to intensify the analgesic effects in the sense of a synergistic effect in order to reduce the dose of analgesic or antiphlogistic and morphine.
- Flupirtin is an analgesic with a muscle relaxant component.
- the object of the invention is to provide improved medicaments with analgesic activity which have a greatly reduced or no addiction potential at all.
- the weight amounts given in the patent claims and in the description always refer to the free bases.
- flupirtine is the type of addiction caused by other compounds such as barbiturate, alcohol, amphetamine, cocaine, cannabis or hallucinogen Withdrawal symptoms can be eliminated or significantly reduced.
- the medicinal product contains, for example, 10 mg to 1000 mg of flupirtine in the form of a pharmaceutically acceptable salt and 5 mg to 500 mg of morphine in the form of a pharmaceutically acceptable salt in a tablet and preferably 50 mg - 500 mg of flupirtine and 10 mg - 250 mg of morphine.
- hydrochloric acid, gluconic acid, malonic acid and maleic acid are suitable as salt formers; in the case of morphine, mineral acids, such as, for example, hydrochloric acid and sulfuric acid, are suitable.
- the medicament according to the invention can be in the form of tablets, capsules, pellets, granules, ampoules for intravenous and intramuscular injection, in the form of infusion solutions and suppositories.
- the pharmaceuticals are produced in a known manner, using the known and customary pharmaceutical auxiliaries and other customary excipients and diluents.
- auxiliaries are, for example, those substances which are recommended or indicated in the following literature as auxiliaries for pharmacy, cosmetics and related fields: Ullmanns Encyklopadie der Technische Chemie, Volume 4 (1953), pages 1 to 39; Journal of Pharmaceutical Sciences, Volume 52 (1963), page 918 et seq., HvCzetsch-Lindenwald, auxiliaries for pharmacy and neighboring areas; Pharm. Ind., Issue 2, 1961, page 72 et seq .; Dr. HP Fiedler, Lexicon of auxiliaries for pharmacy, cosmetics and related areas, 2nd edition, Editio Cantor, Aulendorf in negotiated 1981 and pharmaceutical technology (Hrgs. Fuchs, Sucker, Chapterr, Georg Thieme Verlag, 2nd edition (1991).
- Figure 1 describes the development of tolerance over 45 days of the combination compared to the individual substances.
- Figure 2 shows the antinociaptive effect of the combination compared to the individual substances.
- Figure 3 shows the results of an experiment on psychological dependence.
- FIG. 4 shows, on the basis of the erection frequency of rats, the excitatory effect of morphine alone and the non-excitatory effect of the combination according to the invention.
- FIG. 5 shows an experiment similar to FIG. 4: here the distance is measured as a measure of the excitement of the animals.
- FIG. 6 shows the influence of the individual substances on muscle relaxation in comparison to the combination according to the invention.
Abstract
Description
Das aus Opium, dem eingetrockneten Milchsaft unreifer Mohnkapseln (Papaver somniferum), gewonnene Morphin ist seit seiner Isolierung durch Sertürner (1806) in Form des Hydrochlorids als Mittel gegen starke Schmerzen im Gebrauch. Bei häufigem und lang andauerndem Gebrauch dieses Analgetikums, beispielsweise bei Tumorpatienten, besteht die Gefahr der Ausbildung einer Sucht und Toleranzentwicklung (Morphinismus).The morphine obtained from opium, the dried milk juice of unripe poppy capsules (Papaver somniferum), has been used since its isolation by Sertürner (1806) in the form of the hydrochloride as a remedy for severe pain. With frequent and prolonged use of this analgesic, for example in tumor patients, there is a risk of developing an addiction and developing tolerance (morphinism).
Aber auch die beim bestimmungsgemäßen Gebrauch zu beobachtenden Nebenwirkungen wie beispielsweise euphorische Wirkung, emetische Wirkung, spastische Obstipation und Erhöhung des Tonus der glatten Muskulatur reduzieren die therapeutische Anwendbarkeit von Morphium.
So hat es nicht an Bemühungen gefehlt, stark wirkende, aber nebenwirkungsarme Analgetika synthetisch darzustellen. Das partial synthetische Produkt Diamorphin (Heroin) ist zwar 10mal wirksamer als Morphin, ruft aber wesentlich leichter Sucht hervor. Pethidin ist ca. 5mal schwächer wirksam als Morphin und ist auch weniger spasmogen.However, the side effects observed when used as intended, such as euphoric effects, emetic effects, spastic constipation and increased smooth muscle tone, also reduce the therapeutic applicability of morphine.
There has been no lack of efforts to synthesize strong-acting but low-side-effects analgesics. The partial synthetic product diamorphine (heroin) is 10 times more effective than morphine, but it causes addiction much easier. Pethidine is about 5 times weaker than morphine and is also less spasmogenic.
Auch Pentazocin und Buprenorphin unterliegen auf Grund ihres Suchtpotentials dem Betäubungsmittelrecht.Pentazocin and buprenorphine are also subject to narcotics law due to their addictive potential.
Tramadol ist nur etwa 1/10 - 1/5 so stark wirksam wie Morphin, dafür besitzt es bis jetzt noch kein bekanntgewordenes Suchtpotential.Tramadol is only about 1/10 - 1/5 as potent as morphine, but so far it has no known addiction potential.
Es besteht also immer noch ein großer Bedarf nach einer zuverlässig, auch bei starken Schmerzen gut wirksamen analgetischen Medikation mit wenig Nebenwirkungen, die aus sozialen Gründen kein Suchtpotential aufweisen sollte.There is therefore still a great need for a reliable analgesic medication which is effective even with severe pain and has few side effects and which, for social reasons, should not have any addiction potential.
Um den Verbrauch an Analgetika zu senken, oder um die nicht immer ausreichende analgetische Wirkung zu verstärken, hat man den Weg der Kombination von Wirkstoffen beschritten.
Man versucht dabei, durch Kombination von ausgewählten Analgetika mit Morphin die Nebenwirkungen des Morphin weniger stark in Erscheinung treten zu lassen und die analgetische Wirkung zu verstärken.In order to reduce the consumption of analgesics or to increase the analgesic effect, which is not always sufficient, the combination of active ingredients has been taken.
By trying to combine selected analgesics with morphine, the side effects of morphine are less apparent and the analgesic effect is enhanced.
Da Morphin keine entzündungshemmende Wirkung hat, kann man dieses Defizit in der Morphinwirkung durch Kombination von Morphin mit antiphlogistisch oder antipyretisch wirkenden Analgetika ausgleichen. So beschreiben Vergoni et al. (Life Sci., 50(16), Seite 135-138 (1992)) die potenzierenden Effekte von Pinacidil auf den analgetischen Effekt von Morphin.Since morphine has no anti-inflammatory effect, this deficit in the morphine effect can be compensated for by combining morphine with anti-inflammatory or anti-pyretic analgesics. For example, Vergoni et al. (Life Sci., 50 (16), pages 135-138 (1992)) the potentiating effects of pinacidil on the analgesic effect of morphine.
Eine Kombination aus rektal verabreichten Indomethacin mit intravenös verabreichten Morphin wird von Segstro und Morley-Forster im Can. J. Anaesth. 38(5), 578-581 (1991) beschrieben.A combination of rectally administered indomethacin with intravenously administered morphine is described by Segstro and Morley-Forster in Can. J. Anesth. 38 (5), 578-581 (1991).
Tierversuche, die die Potenzierung von analgetischen Effekten von Morphin und Clonidin an Ratten beschreiben, werden von Wilcox, Carlsson, Jochim und Jurna in Brain Res. 405(1), 84-93 (1987) dargestellt.Animal experiments describing the potentiation of analgesic effects of morphine and clonidine on rats are presented by Wilcox, Carlsson, Jochim and Jurna in Brain Res. 405 (1), 84-93 (1987).
Alle Versuche haben zum Ziel, die analgetischen Wirkungen im Sinne einer synergistischen Wirkung zu verstärken, um die Dosis an Analgetikum beziehungsweise Antiphlogistikum und Morphin zu reduzieren.The aim of all experiments is to intensify the analgesic effects in the sense of a synergistic effect in order to reduce the dose of analgesic or antiphlogistic and morphine.
Flupirtin (INN) ist ein Analgetikum mit muskelrelaxierender Wirkkomponente. (B. Nickel, V. Jakovlev, I. Szelenyi, Arzneim.-Forsch. 40(II)8, 909-911 (1990) DE-OS 36 01 195).Flupirtin (INN) is an analgesic with a muscle relaxant component. (B. Nickel, V. Jakovlev, I. Szelenyi, Arzneimittel-Forsch. 40 (II) 8, 909-911 (1990) DE-OS 36 01 195).
Es verfügt über kein Abhängigkeitspotential.
(B. Nickel, H.O. Barbe, I. Szelenyi, Arzneim.-Forsch. 40(II)8, 905-908 (1990)).
Der antinociceptive Effekt von Flupirtin läßt sich durch Naloxon nicht antagonisieren. Weiterhin zeigt Flupirtin keine Affinität zu Opiat-Rezeptoren.
(B. Nickel, A. Herz, V. Jakovlev, U. Tibes, Arzneim.-Forsch. 35(II), 1402 (1985)).It has no dependency potential.
(B. Nickel, HO Barbe, I. Szelenyi, Arzneimittel-Forsch. 40 (II) 8, 905-908 (1990)).
The antinociceptive effect of flupirtine cannot be antagonized by naloxone. Furthermore, flupirtine shows no affinity for opiate receptors.
(B. Nickel, A. Herz, V. Jakovlev, U. Tibes, Arzneimittel.-Forsch. 35 (II), 1402 (1985)).
Es wurde nun gefunden, daß Flupirtin allein gegeben zu keiner Toleranzentwicklung führt. Überraschend war, daß auch in der Kombination Flupirtin und Morphin alle Anzeichen für eine Toleranzentwicklung fehlten. Dies ist nicht zu erwarten, da sich Flupirtin strukturell stark von den bekannten Morphin-Antagonisten Naloxon oder Methadon unterscheidet.It has now been found that given flupirtine alone does not lead to any development of tolerance. It was surprising that the flupirtine and morphine combination also lacked any signs of tolerance development. This is not to be expected since the structure of flupirtine differs greatly from the known morphine antagonists naloxone or methadone.
Aufgabe der Erfindung ist die Bereitstellung von verbesserten Arzneimitteln mit analgetischer Wirksamkeit, die ein stark reduziertes oder gar kein Suchtpotential mehr aufweisen.
Die in den Patentansprüchen und in der Beschreibung angegebenen Gewichtsmengen beziehen sich immer auf die freien Basen.The object of the invention is to provide improved medicaments with analgesic activity which have a greatly reduced or no addiction potential at all.
The weight amounts given in the patent claims and in the description always refer to the free bases.
Die mehrwöchige Gabe von Flupirtin erzeugt im Tierversuch keine Toleranz. (Figur 1)
Die analgetische Wirkung bleibt über die gesamte Dauer des Versuches (45 Tage) erhalten.The administration of flupirtin for several weeks does not produce tolerance in animal experiments. (Figure 1)
The analgesic effect is retained over the entire duration of the test (45 days).
Die Prüfung erfolgte am Elektroschmerztest an der Ratte (nach Blake et. al Arz. Med. exp. 9, 146 (1963))The test was carried out on the electro pain test on the rat (according to Blake et. Al Arz. Med. Exp. 9 , 146 (1963))
Nach der Einmalgabe von Flupirtin in Kombination mit Morphin kommt es zu einer additiven antinociceptiven Wirksamkeit. (Figur 2)
Die alleinige Gabe von Flupirtin ergibt eine antinociceptive Wirkung von 45 %, die Gabe der Kombination ergibt eine Wirkung von 100 %.Addition of flupirtine in combination with morphine leads to an additive antinociceptive activity. (Figure 2)
Flupirtine alone gives an antinociceptive effect of 45%, the combination gives an effect of 100%.
Bei der Prüfung auf physische Abhängigkeit wird das schon öfters beschriebene Abhängigkeitssymptom unter Morphin, Abnahme der Tiergewichte nach Entzug, durch Flupirtin in der Kombination mit Morphin signifikant aufgehoben (Figur 3). Flupirtin hebt beziehungsweise schwächt das physische Abhängigkeitspotential von Morphin ab.When testing for physical dependency, the often described dependency symptom under morphine, decrease in animal weights after withdrawal, is significantly eliminated by flupirtine in combination with morphine (FIG. 3). Flupirtin increases or decreases the physical addiction potential of morphine.
Es ist auch anzunehmen, daß Flupirtin die durch andere Verbindungen wie die des Barbiturat-, Alkohol-, des Amphetamin-, des Cocain-, des Cannabis- oder des Halluzinogen-Typs hervorgerufenen Abhängigkeits- und Entzugssymptome aufhebt beziehungsweise deutlich abschwächt.It is also believed that flupirtine is the type of addiction caused by other compounds such as barbiturate, alcohol, amphetamine, cocaine, cannabis or hallucinogen Withdrawal symptoms can be eliminated or significantly reduced.
Die Prüfung auf das eventuelle Vorliegen einer psychischen Abhängigkeit erfolgte gemäß der Methode Hosoya, Pharmacol. Meth. Tox, 5, 515 (1979).The test for possible psychological dependence was carried out according to the Hosoya, Pharmacol method. Meth. Tox, 5 , 515 (1979).
In derselben Langzeituntersuchung wurde das Verhalten der Tiere am Entzugstag registriert. Es zeigte sich auch in diesem Modell, daß das Verhalten der Tiere nach Entzug von Morphin (Erregung, Rearing) durch Flupirtin in der Kombination deutlich beeinflußt wird (Figur 4,5). Die deutliche Erregung beziehungsweise das Rearingverhalten der Tiere nach Morphin wird in der Kombination mit Flupirtin reduziert und ähnelt eher dem von unbehandelten Kontrolltieren. Auch wird die durch Morphin hervorgerufene Rigidität bei Tieren durch Flupirtin aufgehoben (Figur 6).In the same long-term study, the behavior of the animals was recorded on the day of withdrawal. It was also shown in this model that the behavior of the animals after withdrawal of morphine (excitation, rearing) by flupirtine was significantly influenced in the combination (FIG. 4.5). The clear excitement or the clearing behavior of the animals after morphine is reduced in combination with flupirtine and is more similar to that of untreated control animals. The rigidity caused by morphine in animals is also eliminated by flupirtine (FIG. 6).
Das Arzneimittel enthält beispielsweise in einer Tablette 10 mg bis 1000 mg Flupirtin in Form eines pharmazeutisch verträglichen Salzes und 5 mg bis 500 mg Morphin in Form eines pharmazeutisch verträglichen Salzes und vorzugsweise 50 mg - 500 mg Flupirtin und 10 mg - 250 mg Morphin.The medicinal product contains, for example, 10 mg to 1000 mg of flupirtine in the form of a pharmaceutically acceptable salt and 5 mg to 500 mg of morphine in the form of a pharmaceutically acceptable salt in a tablet and preferably 50 mg - 500 mg of flupirtine and 10 mg - 250 mg of morphine.
Als Salzbildner kommen im Falle des Flupirtins beispielsweise Salzsäure, Gluconsäure, Malonsäure und Maleinsäure in Frage, im Falle des Morphins kommen Mineralsäuren, wie beispielsweise Salzsäure und Schwefelsäure in Betracht.In the case of flupirtine, for example, hydrochloric acid, gluconic acid, malonic acid and maleic acid are suitable as salt formers; in the case of morphine, mineral acids, such as, for example, hydrochloric acid and sulfuric acid, are suitable.
Das erfindungsgemäße Arzneimittel kann in Form von Tabletten, Kapseln, Pellets, Granulaten, Ampullen zur intravenösen und intramuskulären Injektion, in Form von Infusionslösungen und Zäpfchen vorliegen.
Die Herstellung der Arzneimittel erfolgt in bekannter Weise, wobei die bekannten und üblichen pharmazeutischen Hilfstoffe sowie sonstige übliche Träger- und Verdünnungsstoffe verwendet werden.The medicament according to the invention can be in the form of tablets, capsules, pellets, granules, ampoules for intravenous and intramuscular injection, in the form of infusion solutions and suppositories.
The pharmaceuticals are produced in a known manner, using the known and customary pharmaceutical auxiliaries and other customary excipients and diluents.
Als deraritge Träger- und Hilfsstoffe kommen zum Beispiel solche Stoffe in Frage, die in folgenden Literaturstellen als Hilfsstoffe für Pharmazie, Kosmetik und angrenzende Gebiete empfohlen beziehungsweise angegeben sind: Ullmanns Encyklopädie der technischen Chemie, Band 4 (1953) , Seite 1 bis 39; Journal of Pharmaceutical Sciences, Band 52 (1963), Seite 918 u.ff.,
H.v.Czetsch-Lindenwald, Hilfsstoffe für Pharmazie und angrenzende Gebiete; Pharm. Ind., Heft 2, 1961, Seite 72 u.ff.; Dr. H. P. Fiedler, Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und angrenzende Gebiete, 2. Auflage, Editio Cantor, Aulendorf in Württemberg 1981 und Pharmazeutische Technologie (Hrgs. Fuchs, Sucker, Speiser, Georg Thieme Verlag, 2. Auflage (1991).Suitable deraritge carriers and auxiliaries are, for example, those substances which are recommended or indicated in the following literature as auxiliaries for pharmacy, cosmetics and related fields: Ullmanns Encyklopadie der Technische Chemie, Volume 4 (1953),
HvCzetsch-Lindenwald, auxiliaries for pharmacy and neighboring areas; Pharm. Ind.,
Figur 1 beschreibt die Toleranzentwicklung über 45 Tage der Kombination im Vergleich zu den Einzelstoffen.Figure 1 describes the development of tolerance over 45 days of the combination compared to the individual substances.
Figur 2 zeigt die antinociaptive Wirkung der Kombination im Vergleich zu den Einzelstoffen.Figure 2 shows the antinociaptive effect of the combination compared to the individual substances.
Figur 3 stellt die Ergebnisse eines Versuchs zur psychischen Abhängigkeit dar.Figure 3 shows the results of an experiment on psychological dependence.
Figur 4 zeigt anhand der Aufrichthäufigkeit von Ratten die erregende Wirkung von Morphin alleine und die nicht erregende Wirkung der erfindungsgemäßen Kombination.FIG. 4 shows, on the basis of the erection frequency of rats, the excitatory effect of morphine alone and the non-excitatory effect of the combination according to the invention.
Figur 5 zeigt einen ähnlichen Versuch wie Figur 4: hier wird als Maß für die Erregung der Tiere die Wegstrecke gemessen.FIG. 5 shows an experiment similar to FIG. 4: here the distance is measured as a measure of the excitement of the animals.
Figur 6 zeigt den Einfluß der Einzelsubstanzen auf die Muskelrelaxation im Vergleich zur erfindungsgemäßen Kombination.FIG. 6 shows the influence of the individual substances on muscle relaxation in comparison to the combination according to the invention.
Claims (3)
- Pharmaceutical,
characterised in that
it comprises flupirtine or a pharmaceutically acceptable salt thereof, in a quantity of from 10 mg to 1000 mg, with reference the base, and a pharmaceutically tolerable salt of morphine in a quantity of from 5 mg to 500 mg, with reference to the base. - Method for the preparation of a pharmaceutical according to claim 1,
characterised in that
flupirtine or a pharmaceutically usable salt in a quantity of from 10 mg to 1000 mg together with morphine or a pharmaceutically usable salt thereof in a quantity of from 5 mg to 500 mg together with conventional carriers and auxiliary substances are processed into a pharmaceutical. - Use of a mixture of flupirtine or a pharmaceutically acceptable salt thereof, in a quantity of from 10 mg to 1000 mg, referred to the base, and a pharmaceutically tolerable salt of morphine in a quantity of from 5 mg to 500 mg, with reference to the base, for the preparation of a pharmaceutical.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4236752A DE4236752A1 (en) | 1992-10-30 | 1992-10-30 | Combination preparation of flupirtine and morphine for the treatment of pain and for avoiding morphine addiction |
| DE4236752 | 1992-10-30 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP0595311A1 EP0595311A1 (en) | 1994-05-04 |
| EP0595311B1 true EP0595311B1 (en) | 1997-01-22 |
Family
ID=6471783
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP93117472A Expired - Lifetime EP0595311B1 (en) | 1992-10-30 | 1993-10-28 | Pharmaceutical composition consisting of flupirtin and morphine for the treatment of pain and to avoid a morphine addiction |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US5521178A (en) |
| EP (1) | EP0595311B1 (en) |
| JP (1) | JP3665354B2 (en) |
| AT (1) | ATE147979T1 (en) |
| BR (1) | BR9304431A (en) |
| CA (1) | CA2102072C (en) |
| DE (2) | DE4236752A1 (en) |
| DK (1) | DK0595311T3 (en) |
| ES (1) | ES2099344T3 (en) |
| GR (1) | GR3022995T3 (en) |
| HU (1) | HU219907B (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5843480A (en) | 1994-03-14 | 1998-12-01 | Euro-Celtique, S.A. | Controlled release diamorphine formulation |
| US5849240A (en) | 1993-11-23 | 1998-12-15 | Euro-Celtique, S.A. | Method of preparing sustained release pharmaceutical compositions |
| US5891471A (en) | 1993-11-23 | 1999-04-06 | Euro-Celtique, S.A. | Pharmaceutical multiparticulates |
| US5958452A (en) | 1994-11-04 | 1999-09-28 | Euro-Celtique, S.A. | Extruded orally administrable opioid formulations |
| US6068855A (en) | 1994-11-03 | 2000-05-30 | Euro-Celtique S. A. | Pharmaceutical composition containing a fusible carrier and method for producing the same |
| US6254887B1 (en) | 1993-05-10 | 2001-07-03 | Euro-Celtique S.A. | Controlled release tramadol |
| US7309713B2 (en) | 2005-01-31 | 2007-12-18 | Elbion Ag | Use of the non-opiate analgesic drug flupirtine for the treatment of overactive bladder and associated diseases including urge incontinence, urinary flow problems as a result of prostate hyperplasia and irritable bowel syndrome |
| AU2004298288B2 (en) * | 2003-12-16 | 2011-06-30 | Relevare Aust. Pty Ltd | Methods and compositions |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19918325A1 (en) | 1999-04-22 | 2000-10-26 | Euro Celtique Sa | Extruded drug dosage form, e.g. granulate for tableting, comprising an active agent in a polysaccharide-containing matrix, giving a release profile which is controllable by extrusion conditions and/or the inclusion of additives |
| WO2001008682A2 (en) * | 1999-08-03 | 2001-02-08 | Awd.Pharma Gmbh & Co. Kg | Use of flupirtine for alleviating pain caused by degenerative joint diseases in dogs and cats |
| CA2550023C (en) * | 2003-12-16 | 2011-04-12 | Cnsbio Pty Ltd | Treatment of neuropathic pain |
| US7553858B2 (en) * | 2003-12-17 | 2009-06-30 | Meda Pharma Gmbh & Co. Kg | Combination of flupirtine and tramadol |
| US20060052370A1 (en) * | 2004-08-24 | 2006-03-09 | Meyerson Laurence R | Methods and compositions for treating nociceptive pain |
| US7619007B2 (en) | 2004-11-23 | 2009-11-17 | Adamas Pharmaceuticals, Inc. | Method and composition for administering an NMDA receptor antagonist to a subject |
| WO2006121560A2 (en) | 2005-04-06 | 2006-11-16 | Adamas Pharmaceuticals, Inc. | Methods and compositions for treatment of cns disorders |
| US20070042054A1 (en) * | 2005-04-20 | 2007-02-22 | Council Of Scientific And Industrial Research | Functional aphrodisiac rolled herbal bidis and cigarettes |
| BRPI0719591B1 (en) * | 2006-11-28 | 2018-07-31 | Purac Biochem B.V. | Method for the production of stable lactide particles and the use of said particles |
| US20080279930A1 (en) * | 2007-05-07 | 2008-11-13 | Bernd Terhaag | Controlled-Release Flupirtine Compositions, Compacts, Kits and Methods of Making and Use Thereof |
| US20120059024A1 (en) * | 2009-01-30 | 2012-03-08 | Relevare Aust. Pty Ltd | Drug abuse deterrent, methods and compositions |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FI855016A (en) * | 1985-06-28 | 1986-12-29 | Degussa | SYNERGISTIC COMBINATION AV FLUPIRTIN OCH 4-ACETAMIDO-PHENOL. |
-
1992
- 1992-10-30 DE DE4236752A patent/DE4236752A1/en not_active Withdrawn
-
1993
- 1993-10-27 US US08/141,678 patent/US5521178A/en not_active Expired - Lifetime
- 1993-10-28 ES ES93117472T patent/ES2099344T3/en not_active Expired - Lifetime
- 1993-10-28 DK DK93117472.6T patent/DK0595311T3/en active
- 1993-10-28 AT AT93117472T patent/ATE147979T1/en active
- 1993-10-28 DE DE59305236T patent/DE59305236D1/en not_active Expired - Lifetime
- 1993-10-28 EP EP93117472A patent/EP0595311B1/en not_active Expired - Lifetime
- 1993-10-29 BR BR9304431A patent/BR9304431A/en not_active Application Discontinuation
- 1993-10-29 JP JP27173093A patent/JP3665354B2/en not_active Expired - Lifetime
- 1993-10-29 CA CA002102072A patent/CA2102072C/en not_active Expired - Lifetime
- 1993-10-29 HU HU9303089A patent/HU219907B/en unknown
-
1997
- 1997-04-01 GR GR970400669T patent/GR3022995T3/en unknown
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6254887B1 (en) | 1993-05-10 | 2001-07-03 | Euro-Celtique S.A. | Controlled release tramadol |
| US6162467A (en) | 1993-11-23 | 2000-12-19 | Euro-Celtique, S.A. | Sustained release compositions and a method of preparing pharmaceutical compositions |
| US5849240A (en) | 1993-11-23 | 1998-12-15 | Euro-Celtique, S.A. | Method of preparing sustained release pharmaceutical compositions |
| US5891471A (en) | 1993-11-23 | 1999-04-06 | Euro-Celtique, S.A. | Pharmaceutical multiparticulates |
| US5965163A (en) | 1993-11-23 | 1999-10-12 | Euro-Celtique, S.A. | Substained release compositions and a method of preparing pharmaceutical compositions |
| US5843480A (en) | 1994-03-14 | 1998-12-01 | Euro-Celtique, S.A. | Controlled release diamorphine formulation |
| US6068855A (en) | 1994-11-03 | 2000-05-30 | Euro-Celtique S. A. | Pharmaceutical composition containing a fusible carrier and method for producing the same |
| US5958452A (en) | 1994-11-04 | 1999-09-28 | Euro-Celtique, S.A. | Extruded orally administrable opioid formulations |
| US5965161A (en) | 1994-11-04 | 1999-10-12 | Euro-Celtique, S.A. | Extruded multi-particulates |
| US6261599B1 (en) | 1994-11-04 | 2001-07-17 | Euro-Celtique, S.A. | Melt-extruded orally administrable opioid formulations |
| US6335033B2 (en) | 1994-11-04 | 2002-01-01 | Euro-Celtique, S.A. | Melt-extrusion multiparticulates |
| US6706281B2 (en) | 1994-11-04 | 2004-03-16 | Euro-Celtique, S.A. | Melt-extrusion multiparticulates |
| AU2004298288B2 (en) * | 2003-12-16 | 2011-06-30 | Relevare Aust. Pty Ltd | Methods and compositions |
| US7309713B2 (en) | 2005-01-31 | 2007-12-18 | Elbion Ag | Use of the non-opiate analgesic drug flupirtine for the treatment of overactive bladder and associated diseases including urge incontinence, urinary flow problems as a result of prostate hyperplasia and irritable bowel syndrome |
Also Published As
| Publication number | Publication date |
|---|---|
| DK0595311T3 (en) | 1997-05-26 |
| CA2102072C (en) | 2005-01-04 |
| HU9303089D0 (en) | 1994-01-28 |
| HU219907B (en) | 2001-09-28 |
| ATE147979T1 (en) | 1997-02-15 |
| JP3665354B2 (en) | 2005-06-29 |
| DE4236752A1 (en) | 1994-05-05 |
| JPH06211663A (en) | 1994-08-02 |
| DE59305236D1 (en) | 1997-03-06 |
| CA2102072A1 (en) | 1994-05-01 |
| EP0595311A1 (en) | 1994-05-04 |
| BR9304431A (en) | 1994-06-07 |
| ES2099344T3 (en) | 1997-05-16 |
| HUT66085A (en) | 1994-09-28 |
| US5521178A (en) | 1996-05-28 |
| GR3022995T3 (en) | 1997-07-30 |
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